Pharmacology Research Laboratory, Pharmacology Division, UGC Centre of Advanced Studies, University Institute of Pharmaceutical Sciences (UIPS), Panjab University, Chandigarh, 160014, India.
All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India.
Inflammopharmacology. 2021 Apr;29(2):537-547. doi: 10.1007/s10787-020-00785-5. Epub 2021 Jan 18.
Chronic cerebral hypoperfusion (CCH) induced oxidative stress and inflammation is known to be implicated in the pathogenesis of vascular dementia. The nuclear factor erythroid 2-related factor 2 (Nrf2) has emerged as a potential therapeutic target for neuroprotection. In the present study, we investigated the beneficial effects of dimethyl fumarate (DMF), an Nrf2 activator in an experimental model of vascular dementia.
Permanent occlusion of the bilateral common carotid arteries (2-VO) was performed to induce CCH in adult male Sprague-Dawley rats. DMF (15, 30, and 60 mg/kg) was administered for 4 weeks. Cognitive performance was assessed using the Morris water maze (MWM) and novel object (NOR) tests. After behavior tests, various oxidative and inflammatory markers were assessed in the hippocampus.
The obtained results indicate that treatment with DMF significantly improved 2 VO-induced cognitive deficits. DMF decreased MDA (p < 0.001), protein carbonyl (PCO) contents (p < 0.001), and acetylcholinesterase (p < 0.01) activities, and inhibited inflammatory markers (TNF-α, IL-1β, NF-κβ, and COX-2) levels. Furthermore, our results showed that DMF augmented GSH (p < 0.001) levels and SOD (p < 0.05), CAT, and GSH-Px (p < 0.001) activities in the hippocampus. Nrf2 (p < 0.05) and its downstream targets HO-1 levels (p < 0.01) and NQO1 (p < 0.05) levels were also up-regulated after DMF treatment.
Taken together, the results demonstrate that DMF could serve as a promising neuroprotective agent for treating vascular dementia.
慢性脑灌注不足（CCH）引起的氧化应激和炎症被认为与血管性痴呆的发病机制有关。核因子红细胞 2 相关因子 2（Nrf2）已成为神经保护的潜在治疗靶点。在本研究中，我们研究了 Nrf2 激活剂富马酸二甲酯（DMF）在血管性痴呆实验模型中的有益作用。
通过双侧颈总动脉永久性闭塞（2-VO）诱导成年雄性 Sprague-Dawley 大鼠发生 CCH。给予 DMF（15、30 和 60mg/kg）治疗 4 周。使用 Morris 水迷宫（MWM）和新物体（NOR）测试评估认知表现。行为测试后，评估海马中的各种氧化和炎症标志物。
结果表明，DMF 治疗可显著改善 2-VO 诱导的认知缺陷。DMF 降低 MDA（p<0.001）、蛋白羰基（PCO）含量（p<0.001）和乙酰胆碱酯酶（p<0.01）活性，并抑制炎症标志物（TNF-α、IL-1β、NF-κβ 和 COX-2）水平。此外，我们的结果表明，DMF 增加了海马中的 GSH（p<0.001）水平和 SOD（p<0.05）、CAT 和 GSH-Px（p<0.001）活性。DMF 治疗后，Nrf2（p<0.05）及其下游靶标 HO-1 水平（p<0.01）和 NQO1 水平（p<0.05）也上调。
综上所述，结果表明 DMF 可作为治疗血管性痴呆的有前途的神经保护剂。
